Derivatives of C2-substituted indan-1-ol systems for the prophylaxis or treatment of obesity

ABSTRACT

Derivatives of C2-substituted indan-1-ol compounds of formula I: 
                 
 
its physiologically acceptable salts, and its physiologically functional derivatives for the prophylaxis or treatment of obesity are disclosed herein. Compositions comprising the same, methods for preparing the instant compounds, and methods for reducing weight in mammals and for the prophylaxis or treatment of obesity are also described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No. 10/230,379 filed Aug. 29, 2002, U.S. Pat. No. 6,667,345 which is incorporated herein by reference in its entirety. The instant application takes priority from DE 10142660.7, filed Aug. 31, 2001, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to C2-substituted indan-1-ol systems and their physiologically acceptable salts and physiologically functional derivatives for the prophylaxis or treatment of obesity.

2. Description of the Related Art

EP 0009554 discloses indan-1-one and -1-ol derivatives as herbicides and analgesics.

WO 97/20806 discloses cyclopentyl-substituted indan-1-ol derivatives having inter alia antiinflammatory substances.

SUMMARY OF THE INVENTION

The present invention provides, in a preferred embodiment, compounds which can be used to cause a reduction in weight in mammals and which, in particular, reveal a therapeutically exploitable anorectic action.

In another preferred embodiment, the invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier. Preferably, the composition may further comprise one or more active compounds suitable for reducing weight. Also, the instant invention contemplates those compounds further comprising agents suitable in treating other disorders.

In another preferred embodiment, the instant invention provides a method treating obesity by administering to a subject in need thereof, an effective amount of a compound according to formula I.

In another preferred embodiment, the instant invention provides a method of reducing weight in a mammal, comprising administering to said mammal an effective amount of a compound of formula I.

Additional objects, features and advantages of the invention will be set forth in the description which follows, and in part, will be obvious from the description, or may be learned by practice of the invention. The objects, features and advantages of the invention may be realized and obtained by means of the instrumentalities and combinations particularly pointed out in the appended claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention relates to compounds of the formula (I)

in which

R1, R2, R3, and R4, independently of one another, are H, F, Cl, Br, I, CN, N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl, O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂-NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl, CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, wherein the alkyl, alkenyl and alkynyl groups, in each case one to seven hydrogen the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms may be replaced by fluorine;

or one hydrogen may be replaced by OH, OC(O)CH₃, O—CH₂-Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂;

-   -   phenyl, 1- or 2-naphthyl, 5-tetrazolyl,         1-[(C₁-C₆)-alkyl]-5-tetrazolyl, 2-[(C₁-C₆)-alkyl]-5-tetrazolyl,         1-imidazolyl, 1- or 4-[1,2,4]-triazolyl, 2- or 3-thienyl, 2- or         3-furyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-oxazolyl, 3-, 4- or         5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl,         where the aryl radical or heterocycle may be substituted up to         two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃,         O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂,         NH—SO₂—(C₁-C₄)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂ and         wherein the alkyl groups, one to seven hydrogen atoms may be         replaced by fluorine;     -   or R2 and R3 together form the group —O—CH₂—O—     -   X is S, SO, SO₂;     -   Y is (CH₂)_(p), where p may be 0, 1, 2 or 3;     -   R5 is CF₃, (C₁-C₁₈)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl         groups one to seven hydrogen atoms may be replaced by fluorine;     -   (CH₂)_(r)—COR6, where r=1-6 and R6 may be OH, O—(C₁-C₆)-alkyl or         NH₂;     -   CH₂—CH(NHR7)-COR8, where R7 may be H or C(O)—(C₁-C₄)-alkyl and         R8 may be OH, O—(C₁-C₆)-alkyl or NH₂;     -   phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical,         where the rings or ring systems may be substituted up to two         times by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl,         O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl,         O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl,         S(O)₀₋₂(C₃-C₈)-cycloalkyl NH₂, NH—(C₁-C₈)-alkyl,         NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂,         N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl,         NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,         SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl,         NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl,         COOH, CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂,         CO—NH(C₁-C₈)-alkyl, CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl,         (C₃-C₈)-cycloalkyl, wherein the alkyl groups, in each case one         to seven hydrogen atoms may be replaced by fluorine;     -   R9 is (C₁-C₁₂)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl         radicals one to seven hydrogen atoms may be replaced by         fluorine;     -   CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl, C(O)—(C₁-C₈)-alkyl,         C(O)—(C₃-C₈)-cycloalkyl, C(O)-phenyl,         C(O)—CH(NHR12)—(C₁-C₈)-alkyl, phenyl, 1- or 2-naphthyl,         biphenyl, 2-, 3- or 4-pyridyl, where the aryl or heteroaryl         radicals may be substituted up to two times by F, Cl, Br, CN,         OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl,         NH₂, NH—SO₂—(C₁-C₄)-alkyl, —CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl,         COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂;     -   (CH₂)—R10;     -   (CH₂)_(s)—R11, where s=2 or 3;     -   R10 is (C₁-C₁₂)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl         radicals one to seven hydrogen atoms may be replaced by         fluorine;     -   COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl;     -   phenyl, 1- or 2-naphthyl, biphenyl, 2-, 3- or 4-pyridyl, 2- or         3-furyl or 2- or 3-thienyl, where the aryl or heteroaryl         radicals may be substituted up to two times by F, Cl, Br, CN,         OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl,         NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl,         COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂;     -   R11 is (C₁-C₁₂)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl         radicals one to seven hydrogen atoms may be replaced by         fluorine;     -   COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl; phenyl,         1- or 2-naphthyl, biphenyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl,         2- or 3-thienyl or 1-imidazolyl, where the aryl or heteroaryl         radicals may be substituted up to two times by F, Cl, Br, CN,         OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl,         NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl,         COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂;     -   R12 is H, C(O)—(C₁-C₆)-alkyl;     -   and their physiologically acceptable salts.     -   In a preferred embodiment, the invention provides compounds of         the formula I in which     -   R1 and R4, independently of one another, are H, F, Cl, Br, N₃,         O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl and wherein the alkyl groups, one         to seven hydrogen atoms may be replaced by fluorine;     -   R2 and R3, independently of one another, are H, F, Cl, Br, N₃,         O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl and wherein the alkyl groups, one         to seven hydrogen atoms may be replaced by fluorine;     -   wherein each case at least one of the radicals R1, R2, R3 and R4         is different from hydrogen;     -   X is S, SO, SO₂;     -   Y is (CH₂)_(p), wherein p can be 0, 1, 2 or 3;     -   R5 is (C₁-C₁₈)-alkyl; (C₃-C₄- and C₆-C₈)-cycloalkyl, wherein the         alkyl groups, one to seven hydrogen atoms may be replaced by         fluorine;     -   (CH₂)_(r)—COR6, where r=1-6 and R6 can be OH, O—(C₁-C₆)-alkyl or         NH₂;     -   CH₂—CH(NHR7)-COR8, where R7 can be H or C(O)—(C₁-C₆)-alkyl and         R8 can be OH, O—(C₁-C₆)-alkyl or NH₂;     -   phenyl, 1- or 2-naphthyl, biphenyl or a heterocyclic radical,         where the rings or ring systems may be substituted up to two         times by O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl,         O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl,         S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂,         NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂,         N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl,         NH—CO—(C₃-C₈)-cycloalkyl; SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl,         SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂; NH—SO₂—(C₁-C₈)-alkyl,         NH—SO₂—(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl,         COOH, CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂,         CO—NH(C₁-C₈)-alkyl, CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl,         (C₃-C₈)-cycloalkyl, wherein the alkyl groups in each case one to         seven hydrogen atoms may be replaced by fluorine;     -   F, Cl, Br, I, CN;     -   R9 is (C₁-C₁₂)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl         radicals, one to seven hydrogen atoms may be replaced by         fluorine;     -   CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl, C(O)—(C₁-C₈)-alkyl,         C(O)—(C₃-C₈)-cycloalkyl, C(O)-phenyl,         C(O)—CH(NHR12)-(C₁-C₈)-alkyl, phenyl, 1- or 2-naphthyl,         biphenyl, 2-, 3- or 4-pyridyl, where the aryl or heteroaryl         radicals may be substituted up to two times by F, Cl, Br, CN,         OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl,         NH₂, NH—SO₂—(C₁-C₄)-alkyl, —CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl,         COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂;     -   (CH₂)—R10;     -   (CH₂)_(s)—R11, where s=2 or 3;     -   R10 is (C₁-C₁₂)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl         radicals, one to seven hydrogen atoms may be replaced by         fluorine;     -   COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl;     -   phenyl, 1- or 2-naphthyl, biphenyl, 2-, 3- or 4-pyridyl, 2- or         3-furyl or 2- or 3-thienyl, where the aryl or heteroaryl         radicals may be substituted up to two times by F, Cl, Br, CN,         OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl,         NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl,         COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂;     -   R11 is (C₁-C₁₂)-alkyl, (C₃-C₈)-cycloalkyl, wherein the alkyl         radicals one to seven hydrogen atoms may be replaced by         fluorine;     -   COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl;     -   phenyl, 1- or 2-naphthyl, biphenyl, 2-, 3- or 4-pyridyl, 2- or         3-furyl, 2- or 3-thieny or 1-imidazolyl, where the aryl or         heteroaryl radicals may be substituted up to two times by F, Cl,         Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl,         S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH,         O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂;     -   R12 is H, C(O)—(C₁-C₆)-alkyl;     -   and their physiologically acceptable salts.     -   In another preferred embodiment, the invention provides         compounds of the formula I in which     -   R1 and R4, independently of one another, are H, F, Cl, Br, N3,         O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl, wherein the alkyl groups one to         seven hydrogen atoms may be replaced by fluorine;     -   R2 and R3, independently of one another, are H, F, Cl, Br, N₃,         O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl, wherein the alkyl groups one to         seven hydrogen atoms may be replaced by fluorine;     -   wherein each case at least one of the radicals R1, R2, R3 and R4         is different from hydrogen;     -   X is S, SO, SO₂;     -   Y is (CH₂)_(p), where p is 0 or 1;     -   R5 is (C₁-C₈)-alkyl, wherein the alkyl groups one to seven         hydrogen atoms may be replaced by fluorine;     -   phenyl, where the phenyl radical may be substituted up to two         times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl;     -   R9 is (C₁-C₁₂)-alkyl, wherein the alkyl radicals one to seven         hydrogen atoms may be replaced by fluorine;     -   CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl, C(O)—(C₁-C₈)-alkyl,         C(O)—(C₃-C₈)-cycloalkyl, C(O)-phenyl, where the phenyl radical         may be substituted up to two times by F, Cl, Br, CN, OH,         (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂,         NH—SO₂—(C₁-C₄)-alkyl, —CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH,         CO—O—(C₁-C₄)-alkyl, CO—NH₂;         and their physiologically acceptable salts.

The invention also contemplates compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers, and also to their diastereomers and mixtures thereof.

The alkyl, alkenyl, and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be straight-chain or branched.

Preferred heterocycles or heterocyclic radicals are:

heteroaryls, such as benzimidazolyl, 1-[(C₁-C₆)-alkyl]benzimidazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, benzoxazolyl, benzothiazolyl, 2-, 3- or 4-pyridyl, pyrimidinyl, 4-, 5- or 6-pyridazin-2H-yl-3-one, 4-, 5- or 6-pyridazin-2-(C₁-C₈)-alkyl-2H-yl-3-one, 2-benzyl-4-, -5- or -6-pyridazin-2H-yl-3-one, 3- or 4-pyridazinyl, 2-, 3-, 4- or 8-quinolinyl, 1-, 3- or 4-isoquinolinyl, 1-phthalazinyl, 3- or 4-cinnolinyl, 2- or 4-quinazolinyl, 2-pyrazinyl, 2-quinoxalinyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1-[(C₁-C₆)-alkyl]-2-, -4- or -5-imidazolyl, 3-, 4- or 5-pyrazolyl, 1-[(C₁-C₆)-alkyl]-3-, -4- or -5-pyrazolyl, 1- or 4-[1,2,4]-triazolyl, 4- or 5-[1,2,3]-triazolyl, 1-[(C₁-C₆)-alkyl]-4- or -5-[1,2,3]-triazolyl, 3-, 4- or 7-indolyl, N-[(C₁-C₆)-alkyl]-3-, -4- or -7-indolyl 2-[(C₁-C₆)-alkyl]-3(2H)-indazolyl, 1-[(C₁-C₆)-alkyl]-3(1H)-indazolyl, 5-tetrazolyl, 1-[(C₁-C₆)-alkyl]-1H-tetrazolyl, 2-[(C₁-C₆)-alkyl]-2H-tetrazolyl.

Pharmaceutically acceptable salts are particularly suitable for medical applications, due to their greater solubility in water compared with the starting or base compounds. Said salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula I are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid, and sulfuric acid, and also of organic acids such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid and, additionally L-ascorbic acid, salicylic acid, 1,2-benzisothiazol-3(2H)-one and 6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide. For medicinal purposes, particular preference is given to using the chlorine salt. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and calcium salts).

Salts having a pharmaceutically unacceptable anion are likewise included within the scope of the present invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic applications, for example in vitro applications.

-   -   R1, R2, R3, R4, independently of one another, are H, F, Cl, Br,         N₃, O(C₁-C₈)-alkyl, (C₁-C₈)-alkyl and wherein the alkyl groups         one to seven hydrogen atoms may be replaced by fluorine;     -   wherein each case at least one of the radicals R1, R2, R3 and R4         is different from hydrogen;     -   X is SO₂;     -   Y is (CH₂)_(p), wherein p may be 0,1 or 2;     -   R5 is (C₁-C₈)-alkyl, wherein the alkyl group up to seven         hydrogen atoms may be replaced by fluorine;     -   R6 is F, Cl, Br, CN, (C₁-C₈)-alkyl, wherein the alkyl group up         to seven hydrogen atoms may be replaced by fluorine;     -   R7 is H, (C₁-C₁₂)-alkyl, wherein the alkyl group up to seven         hydrogen atoms may be replaced by fluorine;     -   R8 is (C₁-C₁₂)-alkyl, wherein the alkyl group up to seven         hydrogen atoms may be replaced by fluorine;         and their physiologically acceptable salts.

The invention also contemplates compounds of the formula I in the form of their racemates, racemic mixtures and pure enantiomers, and also to their diastereomers and mixtures thereof.

The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 can be straight-chain or branched.

Heterocycle or heterocyclic radical is to be understood as meaning ring systems which, in addition to carbon, also contain heteroatoms, such as, for example, nitrogen, oxygen or sulfur. This definition furthermore includes ring systems in which the heterocycle or heterocyclic radical is fused with benzene rings.

Preferred heterocycles or heterocyclic radicals are:

heteroaryls, such as benzimidazolyl, 1-[(C₁-C₆)-alkyl]benzimidazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-furyl, benzoxazolyl, benzothiazolyl, 2-, 3- or 4-pyridyl, pyrimidinyl, 4-, 5- or 6-pyridazin-2H-yl-3-one, 4-, 5- or 6-pyridazin-2-(C₁-C₈)-alkyl-2H-yl-3-one, 2-benzyl-4-, -5- or -6-pyridazin-2H-yl-3-one, 3- or 4-pyridazinyl, 2-, 3-, 4- or 8-quinolinyl, 1-, 3- or 4-isoquinolinyl, 1-phthalazinyl, 3- or 4-cinnolinyl, 2- or 4-quinazolinyl, 2-pyrazinyl, 2-quinoxalinyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1-[(C₁-C₆)-alkyl]-2-, -4- or -5-imidazolyl, 3-, 4- or 5-pyrazolyl, 1-[(C₁-C₆)-alkyl]-3-, -4- or -5-pyrazolyl, 1- or 4-[1,2,4]triazolyl, 4- or 5-[1,2,3]triazolyl, 1-[(C₁-C₆)-alkyl]-4- or -5-[1,2,3]triazolyl, 3-, 4- or -7-indolyl, N-[(C₁-C₆)-alkyl]-3-, -4- or -7-indolyl 2-[(C₁-C₆)-alkyl]-3(2H)-indazolyl, 1-[(C₁-C₆)-alkyl]-3(1H)-indazolyl, 5-tetrazolyl, 1-[(C₁-C₆)-alkyl]-1H-tetrazolyl, 2-[(C₁-C₆)-alkyl]-2H-tetrazolyl.

Pharmaceutically acceptable salts are particularly suitable for medical applications, due to their greater solubility in water compared with the starting or base compounds. Said salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula I are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid, and sulfuric acid, and also of organic acids such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid, furthermore L-ascorbic acid, salicylic acid, 1,2-benzisothiazol-3(2H)-one and 6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide. For medicinal purposes, particular preference is given to using the chlorine salt. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

Salts having a pharmaceutically unacceptable anion are likewise included within the scope of the present invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic applications, for example in vitro applications.

The term “physiologically functional derivative” used herein relates to any physiologically acceptable derivative of an inventive compound, for example, an ester which on administration to a mammal, for example, humans, is capable of forming (directly or indirectly) such a compound or an active metabolite thereof.

A further aspect of this invention is the use of prodrugs of the compounds of the formula I. Such prodrugs may be metabolized in vivo to a compound of the formula I. These prodrugs may or may not be active themselves.

The physiologically functional derivatives furthermore include, for example, glucuronides, sulfuric acid esters, glycosides and ribosides.

The compounds of the formula I may also be present in various polymorphous forms, for example, as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the formula I are included within the scope of the invention and are another aspect of the invention.

All references to “compound(s) according to formula (I)” refer hereinbelow to a compound/compounds of the formula (I) as described above and also to their salts, solvates and physiologically functional derivatives as described herein.

A “subject” may be a mammal, and is preferably a human.

The amount and effective amount of a compound according to formula (I) which is required in order to attain the desired biological effect depends on a number of factors, for example, the specific compound selected, the intended use, the type of administration and the clinical state of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example, 3-10 mg/kg/day. An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg/kg and can be administered in a suitable manner as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Individual doses may contain, for example, from 1 mg to 10 g of the active compound. Thus, ampules for injections can contain, for example, from 1 mg to 100 mg, and orally administerable individual dose formulations such as, for example, tablets or capsules can contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the above mentioned masses relate to the mass of the benzothiazepine ion on which the salt is based. The compound used for the prophylaxis or therapy of the above mentioned conditions may be the compounds according to formula (I) themselves, but they are preferably present in the form of a pharmaceutical composition together with an acceptable carrier. The carrier must be naturally acceptable, in the sense that it is compatible with the other ingredients of said composition and is not harmful to the patient's health. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as an individual dose, for example, as a tablet which may contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances may also be present, including further compounds according to formula (I). The pharmaceutical compositions of the invention may be prepared according to any of the known pharmaceutical methods which essentially comprise mixing the ingredients with pharmacologically acceptable carriers and/or excipients.

Pharmaceutical compositions of the invention are those which are suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal, or intravenous) administration, although the most suitable manner of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound according to formula (I) used in each case. Sugar-coated formulations and sugar-coated delayed-release formulations are also included within the scope of the invention. Preference is given to acid-resistant and enteric formulations. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be present in separate units as, for example, capsules, cachets, lozenges, or tablets, which in each case contain a particular amount of the compound according to formula (I); as powders or granules; as solutions or suspensions in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, said compositions may be prepared according to any suitable pharmaceutical method which includes a step in which the active compound and the carrier (which may comprise one or more additional components) are contacted. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely dispersed solid carrier, after which the product is shaped, if necessary. Thus, a tablet, for example, may be prepared by pressing or shaping a powder or granules of the compound, where appropriate, with one or more additional components. Pressed tablets may be prepared by tableting the compound in free-flowing form, for example, a powder or granules, mixed, where appropriate, with a binder, lubricant, inert diluent and/or one or more surface active/dispersing agents in a suitable machine. Shaped tablets can be prepared by shaping the pulverulent compound, moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual) administration include lozenges which contain a compound according to formula (I) with a flavoring, usually sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula (I) which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although they may also be administered subcutaneously, intramuscularly or intradermally as an injection. Said preparations may preferably be prepared by mixing the compound with water and rendering the obtained solution sterile and isotonic with the blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration are preferably present as individual dose suppositories. These may be prepared by mixing a compound according to formula (I) with one or more conventional solid carriers, for example, cocoa butter, and shaping the resulting mixture.

Suitable pharmaceutical compositions for topical application to the skin are preferably present as an ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which may be used are petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations of two or more of these substances. In general, the active compound is present at a concentration of from 0.1 to 15%, for example from 0.5 to 2%, by weight of the composition.

Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal administration may be present as individual patches which are suitable for long-term close contact with the epidermis of the patient. Such patches suitably contain the active compound in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active compound concentration is from approximately 1% to 35%, preferably approximately 3% to 15%. A particular possibility is the release of the active compound by electrotransport or iontophoresis, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986).

The invention furthermore provides a process for preparing the compounds of the formula I which comprises obtaining the compounds of the formula I by proceeding according to the reaction scheme below:

To this end, compounds of the formula II,

in which R1, R2, R3 and R4 are, as defined above, converted with a halogen, such as, for example, bromine or chlorine, into a compound of the formula III.

The compounds of the formula III are converted further with metal salts of thiols of the formula H—X—Y—R5, wherein X is sulfur and Y and R5 are as defined above into compounds of the formula IV wherein X=S. These metal salts can be employed as such or they can be generated in solution in situ from the thiol and a base, such as, for example, aqueous sodium hydroxide.

On the other hand, compounds of the formula IV wherein X=S can be obtained by reacting compounds of the formula II with a base, such as, for example, lithium diisopropylamide, for example in tetrahydrofuran, and with a disulfide of the formula R5-Y—X—X—Y—R5 in which R5 and Y are as defined above and X=S; alternatively, instead of the disulfide, it is also possible to use a sulfenyl chloride of the formula Cl—X—Y—R5 wherein X=S and Y and R5 are as defined above (see, for example, D. Seebach et al.; Chem. Ber. 109, 1601-1616 (1976)).

Compounds of the formula X in which X=SO can be prepared, for example, by selective oxidation of the compound of the formula IV in which X=S, using one equivalent of peroxytrifluoroacetic acid (C. G. Venier et al.; J. Org. Chem. 47, 3773 (1982)). The preparation of the sulfoxides from the sulfides can also be carried out using manganese dioxide or chromic acid (D. Edwards et al.; J. Chem. Soc. 1954, 3272). Furthermore suitable for this oxidation is hydrogen peroxide in acetic anhydride (A. V. Sviridova et al.; J. Org. Chem (Russ), English Transl.; 7, 2577 (1971)).

Compounds of the formula V in which X=SO and R6 is not hydrogen can be prepared, for example, by selective oxidation of the compound of the formula IV in which X=S, using one equivalent of peroxytrifluoroacetic acid (C. G. Venier et al.; J. Org. Chem. 47, 3773 (1982)). The preparation of the sulfoxides from the sulfides can also be carried out using manganese dioxide or chromic acid (D. Edwards et al.; J. Chem. Soc. 1954, 3272). Furthermore suitable for this oxidation is hydrogen peroxide in acetic anhydride (A. V. Sviridova et al.; J. Org. Chem (Russ), English Transl.; 7, 2577 (1971)).

Compounds of the formula XI in which X=SO₂ can be obtained by oxidation using, for example, 2KHSO₅×KHSO₄×K₂SO₄ (Oxone), either from compounds of the formula IV in which X=S or from compounds of the formula X in which X=SO (see, for example, M. Hudlický, Oxidations in Organic Chemistry, ACS Monograph 186, American Chemical Society, Washington, D.C., 1990).

Compounds of the formula X in which X=SO or of the formula XI, in which X=SO₂ and Y=a bond (═(CH₂)m where m=0) can also, alternatively, be prepared according to the scheme below (shown for the preparation of the aryl sulfoxides (H. J. Monteiro et al.; Tetrahedron Letters 11, 921-924 (1975) and aryl sulfones (A. K. Maiti et al.; Tetrahedron 50, 10483-10490 (1994)):

By reduction with, for example, lithium aluminum hydride or sodium borohydride, it is possible to convert the ketones of the formula IV in which X=S into the alcohols of the formula VIII in which X=S. In a similar manner, the compounds of the formula X in which X=SO can be converted into the compounds of the formula IX in which X=SO, and the compounds of the formula XI in which X=SO₂ can be converted into those compounds XII in which X=SO₂. Furthermore, compounds of the formula IX in which X=SO can be converted by oxidation into compounds of the formula XII in which X=SO₂. By oxidation, it is also possible to prepare compounds of the formula IX in which X=SO from compounds of the formula VIII in which X=S.

Indenes of the formula VII can be converted by oxidative addition of compounds of the formula HX—Y—R5 in which X=S into compounds of the formula IX in which X=SO (see, for example, J. F. Ford et al. (Tetrahedron 4, 325-336 (1958)).

Compounds of the formula I in which X=S can be obtained by alkylation or acylation from compounds of the formula VIII in which X=S.

Compounds of the formula I in which X=SO can either be prepared by oxidation from compounds of the formula I in which X=S or by alkylation or acylation from compounds of the formula IX in which X=SO.

Compounds of the formula I in which X=SO₂ can be prepared by oxidation of compounds of the formula I in which X=S or SO₂ or by alkylation or by acylation of compounds of the formula XII in which X=SO₂.

Compounds of the formula I in which X=S and the radicals R1 to R9 are as defined can also be prepared by addition of compounds of the type R5-Y—X—H in which X=S to indenes of the formula VII via the chlorine compounds of the formula XIII and subsequent reaction with compounds of the formula H—O—R9 or M—O—R9 where M is, for example, an alkali metal:

Compounds of the formula I in which X=SO₂ can also be obtained by reacting epoxides of the formula XIV with sulfinic acid salts of the formula R5-Y—X—Na, in which X=SO₂ to give compounds of the formula XII in which X=SO₂, which are subsequently subjected to an alkylation or acylation to give compounds of the formula I in which X=SO₂:

Inorganic acids suitable for forming salts are, for example: hydrohalic acids, such as hydrochloric acid and hydrobromic acid, and also sulfuric acid, phosphoric acid and amidosulfonic acid.

Organic acids suitable for salt formation which may be mentioned are, for example: formic acid, acetic acid, benzoic acid, p-toluenesulfonic acid, benzenesulfonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, citric acid, L-ascorbic acid, salicylic acid, isethionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, 1,2-benzisothiazol-3(2H)-one, 6-methyl-1,2,3-oxathiazin-4(3H)-one 2,2-dioxide.

The examples shown below serve to illustrate the invention without limiting it. The melting points or decomposition points (m.p.) measured are uncorrected and generally depend on the heating rate.

TABLE 1 Examples Formula I

Exam- ple R1 R2 R3 R4 X Y R5 R9 m. p. [° C.] 1 H Cl H H SO₂ — CH₃ C(O)CH₃ 136 ¹H NMR (400 MHz, d₆-DMSO δ (CHOCO) [ppm]) 2 H Cl H H SO₂ — CH₃ C(O)—  6.75 (cis) C₆H₄-4-Cl 3 H Cl H H SO₂ — CH₃ C(O)—  6.65 (trans) C₆H₄-4-Cl [MH⁺] 4 H H H H SO — C₆H₅ CO—CH₃ 301.12 (trans- syn) 5 H H H H SO — C₆H₅ CO—CH₃ 301.12 (trans- anti) 6 H H H H SO — C₆H₅ CO—CH₃ 301.12 (cis- anti) 7 H Cl H H S — CH₃ CO—CH₃ 197.3 (MH⁺— CH₃COOH) 8 H N₃ H H SO₂ — CH₃ CO—CH₃ 236.3 (MH⁺— CH₃COOH) 9 H Cl H H SO — CH₃ CO—CH₃ 213.3 (MH⁺— CH₃COOH)

The compounds of the formula I are distinguished by beneficial actions on the metabolism of lipids, and they are particularly suitable for weight reduction and, after weight reduction, for maintaining a reduced weight in mammals and as anorectic agents. Accordingly, the instant compounds are particularly useful for treating obesity by reducing weight, maintaining weight loss, and preventing obesity by, for example, preventing symptoms of weight loss.

The compounds are distinguished by their low toxicity and their few side effects. The compounds may be employed alone or in combination with other weight-reducing or anorectic active compounds. Further anorectic active compounds of this kind are mentioned, for example, in the Rote Liste, Chapter 01, (Arzneimittelverzeichnis für Deutschland, published by Rote Liste Service GmbH, Frankfurt) under weight-reducing agents/appetite suppressants, and may also include those active compounds which increase the energy turnover of the organism and thus lead to weight reduction or else those which influence the general metabolism of said organism such that increased calorie intake does not cause an enlargement of the fat deposits, and a normal calorie intake causes a reduction in the fat deposits of said organism. The compounds are suitable for the prophylaxis and, in particular, for the treatment of problems of excess weight or obesity. The compounds are furthermore suitable for the prophylaxis and, in particular, for the treatment of type II diabetes, arteriosclerosis, the normalization of lipid metabolism, and for the treatment of high blood pressure.

In a further aspect of the invention, the compounds of the formula I may be administered in combination with one or more further pharmacologically active substances which may be selected, for example, from the group consisting of antidiabetics, antiadipose agents, blood-pressure-lowering active compounds, lipid reducers, and active compounds for the treatment and/or prevention of complications caused by diabetes or associated with diabetes.

Suitable antidiabetics include insulins, amylin, GLP-1 and GLP-2 derivatives such as, for example, those disclosed by Novo Nordisk A/S in WO 98/08871 and also oral hypoglycemic active compounds.

Said oral hypoglycemic active compounds preferably include sulfonyl ureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulin sensitizers, activators of insulin receptor kinase, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, for example glycogen phosphorylase inhibitors, modulators of glucose uptake and glucose elimination, lipid metabolism-modifying compounds such as antihyperlipidemic active compounds and antilipidemic active compounds, for example HMGCoA-reductase inhibitors, inhibitors of cholesterol transport/cholesterol uptake, inhibitors of the reabsorption of bile acid or inhibitors of microsomal triglyceride transfer protein (MTP), compounds which reduce food intake, PPAR and RXR agonists and active compounds which act on the ATP-dependent potassium channel of beta cells.

In one embodiment of the present invention, the present compounds are administered in combination with insulin.

In another embodiment, the compounds of the invention are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide, glibornuride or gliclazide.

In another embodiment, the compounds of the present invention are administered in combination with a biguanide such as, for example, metformin.

In another embodiment, the compounds of the present invention are administered in combination with a meglitinide such as, for example, repaglinide.

In yet another embodiment, the compounds of the present invention are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In yet another embodiment, the compounds of the present invention are administered in combination with a monoamine oxidase inhibitor such as disclosed, for example, in WO 01/12176. Particularly suitable for this purpose are [3(S),3a(S)]-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, (R)-5-(methoxymethyl)-3-[6-(4,4,4-trifluorobutoxy)benzofuran-3-yl]oxazolidin-2-one or (R)-5-(methoxymethyl)-3-[6-cyclopropylmethoxybenzofuran-3-yl]oxazolidin-2-one.

In another embodiment, the compounds of the present invention are administered in combination with an α-glucosidase inhibitor such as, for example, miglitol or acarbose.

In yet another embodiment, the present compounds are administered in combination with an hCNTF (human ciliary neurotrophic factor) or derivatives thereof, such as, for example, CNTF_(AX15) or modified CNTF_(AX15), such as disclosed, for example, in Lambert et al., PNAS 98, 4652-4657.

In another embodiment, the compounds of the present invention are administered in combination with an active compound which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.

In yet another embodiment, the compounds of the present invention are administered in combination with an antihyperlipidemic active compound or an antilipidemic active compound such as, for example, cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine.

In another embodiment, the compounds of the present invention are administered in combination with more than one of the aforementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

Furthermore, the compounds of the invention may be administered in combination with one or more antiadipose agents or appetite-controlling active compounds.

Such active compounds may be selected from the group consisting of CART agonists, NPY antagonists, melanocortin 3 or 4 (MC3 or MC4) agonists, melanin-concentrating hormone (MCH) antagonists, orexin antagonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 adrenoceptor agonists, CCK agonists, serotonin re-uptake inhibitors, mixed serotonin and noradrenalin reuptake inhibitors, 5HT modulators, bombesin agonists, galanin antagonists, glucocorticoid receptor modulators, growth hormone, growth-hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin receptor agonists, leptin mimetics, dopamine agonists (bromocriptine, doprexin), lipase/amylase inhibitors, cannabinoid receptor 1 antagonists, modulators of acylation-stimulating protein (ASP), PPAR modulators, RXR modulators or TR-β agonists.

In one embodiment of the invention, the antiadipose agent is leptin or modified leptin.

In another embodiment, the antiadipose agent is dexamphetamine or amphetamine.

In another embodiment, the antiadipose agent is fenfluramine or dexfenfluramine.

In yet another embodiment, the antiadipose agent is sibutramine or the mono- and bis-demethylated active metabolite of sibutramine.

In another embodiment, the antiadipose agent is orlistate.

In another embodiment, the antiadipose agent is mazindol, diethylpropione or phentermine.

Furthermore, the compounds of the present invention may be administered in combination with one or more antihypertensive active compounds. Examples of antihypertensive active compounds are betablockers such as alprenolol, atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin-converting enzyme) inhibitors such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and also alphablockers such as doxazosin, urapidil, prazosin and terazosin. Furthermore, reference may be made to Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, Pa., 1995.

It is self-evident that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is to be regarded as covered by the scope of protection of the present invention.

The formulations below serve to illustrate the invention, without limiting it.

EXAMPLE A

Soft gelatin capsules, comprising 100 mg of active compound per capsule:

per capsule Active compound 100 mg Triglyceride mixture fractionated from coconut butter 400 mg Capsule contents 500 mg

EXAMPLE B

Emulsion, comprising 60 mg of active compound per 5 ml:

per 100 ml of emulsion Active compound 1.2 g Neutral oil q.s. Sodium carboxymethylcellulose 0.6 g Polyoxyethylene stearate q.s. Glycerol pure 0.2 to 2.0 g Flavoring q.s. Water (demineralized or distilled) to 100 ml

EXAMPLE C

Rectal administration form, comprising 40 mg of active compound per suppository:

per suppository Active compound 40 mg Suppository base ad 2 mg

EXAMPLE D

Tablets comprising 40 mg of active compound per tablet:

per tablet Lactose  600 mg Corn starch  300 mg Soluble starch  20 mg Magnesium stearate  40 mg 1000 mg

EXAMPLE E

Coated tablets, comprising 50 mg of active compound per coated tablet:

per coated tablet Active compound  50 mg Corn starch 100 mg Lactose  60 mg Sec calcium phosphate  30 mg Soluble starch  5 mg Magnesium stearate  10 mg Colloidal silica  5 mg 260 mg

EXAMPLE F

For preparing the contents of hard gelatin capsules, the following recipes are suitable:

a) Active compound 100 mg Corn starch 300 mg 400 mg b) Active compound 140 mg Lactose 180 mg Corn starch 180 mg 500 mg

EXAMPLE G

Drops can be prepared according to the following recipe (100 mg of active compound in 1 ml=20 drops):

Active compound 10 g Methyl benzoate 0.07 g Ethyl benzoate 0.03 g Ethanol 96% 5 ml Demineralized water ad 100 ml

The activity of the compounds of the formula I was assayed as follows:

Biological Test Model:

The anorectic action was tested on female NMRI mice. After removal of feed for 24 hours, the preparation to be tested was administered intraperitoneally (ip) or by gavage (po). The animals were housed singly and, with free access to drinking water, they were offered evaporated milk 30 minutes after administration of the preparation. The consumption of evaporated milk was determined and the general behavior of the animals was monitored every half an hour for 7 hours. The measured milk consumption was compared to that of vehicle-treated control animals.

TABLE 2 Anorectic action, measured as a reduction in the cumulative milk consumption by treated animals compared with control animals Compound/Example

  Formula I Dose [mg/kg] Number of animals/ cumulative milk consumption by treated animals N/[ml] Number of animals/ cumulative milk consumption by untreated control animals N/[ml] Reduction in cumulative milk consumption as % of the control Example 1 10 5/0.28 5/1.50 81

The table indicates that the compounds of the formula I exhibit very good anorectic action.

The preparation of some examples is described in detail below; the other compounds of the formula I were obtained analogously:

EXAMPLE 1 1-Acetoxy-5-chloro-2-methylsulfonylindane

1. 5-Chloro-2-methylsulfanylindan-1-one:

0.98 g (4 mmol) of 2-bromo-5-chloroindan-1-one and 0.42 g (6 mmol) of sodium thiomethoxide are suspended in 5 ml of ethanol, treated in an ultrasonic bath for 30 minutes and then stirred at room temperature for 90 minutes. The reaction mixture is concentrated under reduced pressure and chromatographed on silica gel using toluene/ethyl acetate 10/1. The eluates are concentrated under reduced pressure, giving 0.63 g of 5-chloro-2-methylsulfanylindan-1-one of melting point 90° C.

2. 5-Chloro-2-methylsulfonylindan-1-one:

0.5 g (2.35 mmol) of 5-chloro-2-methylsulfanylindan-1-one is dissolved in 10 ml of methanol; at 0° C., a solution of 4.33 g (7.05 mmol) of 2KHSO5×KHSO4×K2SO4 in 10 ml of water is added dropwise. The mixture is stirred at room temperature for 5 h; the methanol is distilled off and the aqueous residue is extracted with dichloromethane. The organic phase is separated off, dried over MgSO4, filtered and concentrated under reduced pressure. This gives 0.5 g of 5-chloro-2-methanesulfonylindan-1-one of melting point 197° C.

3. 5-Chloro-2-methylsulfonylindan-1-ol:

0.489 g (2 mmol) of 5-chloro-2-methylsulfonylindan-1-one and 0.095 g (2.5 mmol) of sodium borohydride are suspended in 10 ml of ethanol and placed in an ultrasonic bath for 4 h. The reaction mixture is then acidified with 2N HCl and stirred. The ethanol is distilled off, water and dichloromethane are added to the residue and the mixture is extracted with dichloromethane. The organic phase is separated off, dried over MgSO₄, filtered and concentrated and the residue is purified chromatographically on silica gel using dichloromethane/methanol 20/1. This gives 5-chloro-2-methylsulfonylindan-1-ol of melting point 163° C.

4. 1-Acetoxy-5-chloro-2-methylsulfonylindane:

0.247 g (1 mmol) of 5-chloro-2-methylsulfonylindan-1-ol is dissolved in 5 ml of dichloromethane. 1 ml of pyridine and 1 ml of acetic anhydride are added to the solution, and the reaction mixture is then stirred at room temperature for 2 days. The reaction solution is concentrated completely and the residue is taken up in dichloromethane and extracted with dilute citric acid. The organic phase is separated off, concentrated and purified chromatographically (silica gel; dichloromethane/methanol 20/1). This gives 1-acetoxy-5-chloro-2-methylsulfonylindane of melting point 136° C.

EXAMPLES 2-3

Reaction of 5-chloro-2-methylsulfonylindan-1-ol with 4-chlorobenzoyl chloride gives cis- and trans-5-chloro-2-methanesulfonylindan-1-yl 4-chlorobenzoate.

EXAMPLES 4-9

Reaction of the corresponding alcohols with acetyl chloride gives the O-acetyl derivatives described.

Additional advantages, features, and modifications will readily occur to those skilled in the art. Therefore, the invention in its broader aspects is not limtied to the specific details shown and described herein. Accordingly, various modifications may be made without departing from the spirit or scope of the general inventive concept as defined by the appended claims and their equivalents.

As used herein and in the following claims, articles such as “the”, “a”, and “an” can connote the singular or the plural.

All documents referred to herein are specifically incorporated herein by reference their entireties.

The instant priority document, DE 10142660.7, filed Aug. 31, 2001, is incorporated herein by reference in its entirety. 

1. A compound of the formula I,

in which R1, R2, R3, R4 independently of one another are H, F, Cl, Br, I, CN; N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl, O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO2-NH₂, NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, O—CH₂—COOH O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl, CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, (C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, wherein the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms may be replaced by fluorine, or one hydrogen may be replaced by OH, OC(O)CH₃, O—CH₂-Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂; phenyl, 1- or 2-naphthyl, where the aryl radical may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂ and wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; X is SO; Y is (CH₂)p, where p may be 0, 1, 2 or 3; R5 is CF₃, (C₁-C₁₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; (CH₂)r COR₆, where r=1-6 and R6 may be OH, O—(C₁-C₆)-alkyl or NH₂; CH₂—CH(NHR7)-COR8, where R7 may be H or C(O)—(C₁-C₄)-alkyl and R8 may be OH, O—(C₁-C₆)-alkyl or NH₂; or phenyl, 1- or 2-naphthyl, or biphenyl, where the rings or ring systems may be substituted up to two times by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloallcyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₆)-cycloalkyl N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloulkyl]₂, NH—-CO—(C₂-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl, CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine; R9 is (C₁-C₁₂)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl, C(O)—(C₁-C₈)-alkyl, C(O)—(C₃-C₈)-cycloalkyl, C(O)-phenyl, C(O)—CH(NHR12)-(C₁-C₈)-alkyl, phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, —CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂; (CH₂)—R10; (CH₂)_(s)—R11, where s=2 or 3; R10 is (C₁-C₁₂)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl; phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂, R11 is (C₁-C₁₂)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl; phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO— O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, or CO—NH₂; R12 is H, or C(O)—(C₁-C₆)-alkyl; with the proviso that when R9 is CO—CH₃, and X is O, and Y is (CH₂)_(p) wherein p is 0, and R5 is phenyl substituted by chloro in the para position, then R1, R2, R3 and R4 cannot all be hydrogen at the same time; and their physiologically acceptable salts.
 2. The compound of formula 1, as claimed in claim 1 where in R1, R4 independently of one another are H, F, Cl, Br, N₃, O(C₁-C₈)-alkyl, or (C₁--C₈)-alkyl and wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; R2, R3 independently of one another are H, F, Cl, Br, N₃, O(C₁-C₈)-alkyl, or (C₁-C₈)-alkyl and wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; wherein in each case at least one of the radicals R1, R2, R3 and R4 is different from hydrogen; X is SO; Y is (CH₂)p, where p can be 0, 1, 2 or 3; R5 is (C₁-C₁₈)-alkyl; (C₃-C₄- or C₆-C₈)-cycloalkyl, wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; (CH₂)_(r)—COR6, where r=1-6 and R6 can be OH, O—(C₁-C₆)-alkyl or NH₂; CH₂—CH(NHR7)-COR8, where R7 can be H or C(O)—(C₁-C₆)-alkyl and R8 can be OH, O—(C₁-C₆)-alkyl or NH₂; or phenyl, 1- or 2-naphthyl, ox biphenyl, where the rings or ring systems may be substituted up to two times by O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cyclaalkyl]₂, NH—CO—(C₂-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H; SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH-SO—NH₂; NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂-(C₃-C₈)-cycloalkyl; O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl, CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, where in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine; F, Cl, Br, I, CN; R9 is (C₁-C₁₂)-alkyl, (C₃-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl, C(O)—(C₁-C₈)-alkyl, C(O)—(C₃-C₈)-cycloalkyl, C(O)-phenyl, C(O)—CH(NHR12)—(C₁-C₈)-alkyl, phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, —CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, or CO—NH₂; (CH₂)-R10; (CH₂)_(s)—R11, where s=2 or 3; R10 is (C₁-C₁₂)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl; phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂; R11 is (C₁-C₁₂)-alkyl, (C₃-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen acorns may be replaced by fluorine; COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl; phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂; R12 is H, or C(O)—(C₁-C₆)-alkyl; and their physiologically acceptable salts.
 3. The compound of formula I, as claimed in claim 1 in which R1, R4 independently of one another are H, F, Cl, Br, N₃, O(C₁-C₈)-alkyl, or (C₁-C₈)-alkyl and wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; R2, R3 independently of one another are H, F, Cl, Br, N₃, O(C₁-C₈)-alkyl, or (C₁-C₈)-alkyl and where in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; where in each case at least one of the radicals R1, R2, R3 and R4 is different from hydrogen; X is SO; Y is (CH₂)_(p), where p is 0 or 1; R5 is (C₁-C₈)-alkyl, wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; phenyl, where the phenyl radical may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, or O—(C₁-C₄)-alkyl; R9 is (C₁-C₁₂)-alkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl, C(O)—(C₁-C₈)-alkyl, C(O)—(C₃-C₈)-cycloalkyl, or C(O)-phenyl, where the phenyl radical may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH2, NH—SO₂—(C₁-C₄)-alkyl-CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄-alkyl, or CO—NH2, and their physiologically acceptable salts.
 4. A pharmaceutical composition comprising an effective amount of a compound of formula II

in which R1, R2, R3, R4, independently of one another, are H, F, Cl, Br, I, CN; N₃, NO₂, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CH₂-phenyl, O-phenyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₁-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl, NH—SO2—NH₂, NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl, CO—N[(C₁-C₈)-alkyl]₂; (C₁-C₈)-alkyl, C₃-C₈)cycloalkyl, (C₂-C₈)-alkenyl, (C₂-C₈)-alkynyl, wherein in the alkyl, alkenyl and alkynyl groups in each case one to seven hydrogen atoms may be replaced by fluorine; or one hydrogen may be replaced by OH, OC(O)CH₃, O—CH₂-Ph, NH₂, NH—CO—CH₃ or N(COOCH₂Ph)₂; phenyl, 1- or 2-naphthyl, where the aryl radical may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl NH₂, NH—SO₂—(C₁-C₄)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂ and wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; X is SO; Y is (CH₂)p, where p may be 0, 1, 2 or 3; R5 is CF₃, (C₁-C₁₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl groups one to seven hydrogen atoms may be replaced by fluorine; (CH₂)r COR₆, where r=2-6 and R6 may be OH, O—(C₁-C₆)-alkyl or NH₂; CH₂—CH(NHB7)-COR8, where R7 may be H or C(O)—(C₁-C₄)-alkyl and R8 may be OH, O—(C₁-C₆)-alkyl or NH₂; or phenyl, 1- or 2-naphthyl, or biphenyl, where the rings or ring systems may be substituted up to two times by F, Cl, Br, I, CN, OH, O(C₁-C₈)-alkyl, O(C₃-C₈)-cycloalkyl, O—CO—(C₁-C₈)-alkyl, O—CO—(C₃-C₈)-cycloalkyl, S(O)₀₋₂(C₁-C₈)-alkyl, S(O)₀₋₂(C₃-C₈)-cycloalkyl, NH₂, NH—(C₁-C₈)-alkyl, NH—(C₃-C₈)-cycloalkyl, N[(C₁-C₈)-alkyl]₂, N[(C₃-C₈)-cycloalkyl]₂, NH—CO—(C₂-C₈)-alkyl, NH—CO—(C₃-C₈)-cycloalkyl; SO₃H, SO₂—NH₂, SO₂—NH—(C₁-C₈)-alkyl, SO₂—NH—(C₃-C₈)-cycloalkyl; NH—SO₂—NH₂, NH—SO₂—(C₁-C₈)-alkyl, NH—SO₂—(C₃-C₈)-cycloalkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O(C₁-C₈)-alkyl, CO—O—(C₃-C₈)-cycloalkyl, CO—NH₂, CO—NH(C₁-C₈)-alkyl, CO—N[(C₁-C₈)-alkyl]₂, (C₁-C₈)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl groups in each case one to seven hydrogen atoms may be replaced by fluorine; R9 is (C₁-C₁₂)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl, C(O)—(C₁-C₈)-alkyl, C(O)—(C₃-C₈)-cycloalkyl, C(O)-phenyl, C(O)—CH(NHR12)-(C₁-C₈)-alkyl, phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, —CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂; (CH₂)—R10; (CH₂)_(s)—R11, where s=2 or 3; R10 is (C₁-C₁₂)-alkyl, or (C₃-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl; phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to two times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH_(2,) NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, CO—NH₂, R11 is (C₁-C₁₂)-alkyl, or (C₁-C₈)-cycloalkyl, wherein in the alkyl radicals one to seven hydrogen atoms may be replaced by fluorine; COOH, CONH₂, CO—O(C₁-C₆)-alkyl, CO—O(C₃-C₈)-cycloalkyl; phenyl, 1- or 2-naphthyl, or biphenyl, where the aryl radicals may be substituted up to twa times by F, Cl, Br, CN, OH, (C₁-C₄)-alkyl, CF₃, O—(C₁-C₄)-alkyl, S(O)₀₋₂(C₁-C₆)-alkyl, NH₂, NH—SO₂—(C₁-C₄)-alkyl, O—CH₂—COOH, O—CH₂—CO—O(C₁-C₈)-alkyl, COOH, CO—O—(C₁-C₄)-alkyl, or CO—NH₂; R12 is H, or C(O)—(C₁-C₆)alkyl; and their physiologically acceptable salts, and a pharmaceutically acceptable carrier thereof.
 5. The pharmaceutical composition according to claim 4, further comprising one or more active compounds suitable for reducing weight or for the treatment of obesity.
 6. The pharmaceutical composition according to claim 4, further comprising one or more of the agents selected from the group consisting of cathine, phenylpropanolamine, amfepramone, mefenorex, ephedrine, leptin, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, mazindol or phentermine and their salts.
 7. A method for the treating obesity, comprising administering to a subject in need thereof, an effective amount of a compound according to formula II as claimed in claim
 4. 8. A method of reducing weight in a mammal, comprising administering to said mammal an effective amount of a compound of formula II as claimed in claim
 4. 9. A method of maintaining weight loss, comprising administering to a subject in need thereof, an effective amount of a compound of formula II as claimed in claim
 4. 10. The method of claim 9, further comprising administering one or more active compound, for reducing weight in mammals. 